Abstract
Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
| Original language | English |
|---|---|
| Pages (from-to) | 212-224 |
| Number of pages | 13 |
| Journal | Cancer Letters |
| Volume | 347 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jun 1 2014 |
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Keywords
- Drug resistance
- FOXO1
- MEK inhibitors
- Ovarian carcinoma
- Platinum compounds
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells. / Cossa, Giacomo; Lanzi, Cinzia; Cassinelli, Giuliana; Carenini, Nives; Arrighetti, Noemi; Gatti, Laura; Corna, Elisabetta; Zunino, Franco; Zaffaroni, Nadia; Perego, Paola.
In: Cancer Letters, Vol. 347, No. 2, 01.06.2014, p. 212-224.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells
AU - Cossa, Giacomo
AU - Lanzi, Cinzia
AU - Cassinelli, Giuliana
AU - Carenini, Nives
AU - Arrighetti, Noemi
AU - Gatti, Laura
AU - Corna, Elisabetta
AU - Zunino, Franco
AU - Zaffaroni, Nadia
AU - Perego, Paola
PY - 2014/6/1
Y1 - 2014/6/1
N2 - Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
AB - Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
KW - Drug resistance
KW - FOXO1
KW - MEK inhibitors
KW - Ovarian carcinoma
KW - Platinum compounds
UR - http://www.scopus.com/inward/record.url?scp=84898457102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84898457102&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2014.02.016
DO - 10.1016/j.canlet.2014.02.016
M3 - Article
VL - 347
SP - 212
EP - 224
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
IS - 2
ER -